From epidemiology to cancer-

preventing vaccines:

the example of HPV

Silvia FranceschiInfections and Cancer Epidemiology Group

International Agency for Research on Cancer

Lyon, France

Milan, 19 March 2007

IARC-ICE 2005

Infection-attributable cancers in 2002

From Parkin, 2006

Developed countries Developing countries

7.7% of all cancers 26.3% of all cancers

Other:

0.2% H.pylori: 7%

HPV: 7.7%

HBV & HCV:

8.2%

EBV: 1.6%

HIV/HHV-8:

1.6%

HIV/HHV-8: 0.3%

EBV: 0.3%

HBV & HCV: 1%

HPV: 2.2%

H.pylori: 3.9%

IARC-ICE 2005

Phylogenetic tree of HPV genotypes

IARC-ICE 2005

China

Lampang

Argentina

IARC Multi-centre HPV Prevalence Surveys

Hanoi

Ho Chi Minh

Korea

Colombia

Nigeria

Spain

Songkla

Chile

Ital

y

ShenzhenMexico

The Netherlands

India

completed ongoing in planning

Mongolia

Algeria

GuineaUganda

Poland

ShenyangShanxiNepal

Kenya

South Africa

Pakistan

Iran

Georgia

IARC-ICE 2005

Prevalence of cervical HPV DNA in sexually active women

IARC Multi-centre HPV Prevalence Survey, 1995-2005

MongoliaNigeriaChina, ShenzhenArgentina IndiaChina, ShenyangColombiaChina, ShanxiChileMexicoKoreaVietnam, Ho Chi Minh Italy, TurinThailand, LampangNetherlandsThailand, SongklaSpain Vietnam, Hanoi

999933534908

1940685

1981671971

1340870918

101310243299

716908

1007

0 5 10 15 20 25 30 35

IARC-ICE 2005

All cases (n=14,097)

0

20

40

60

16 18 33 45 31 58 52 35HPV type

%

Africa (n=1,373)

0

20

40

60

16 18 33 45 35 31 58 52HPV type

%

Asia (n=5,652)

0

20

40

60

16 18 58 33 52 45 31 35HPV type

%

Europe (n=4,334)

0

20

40

60

16 18 33 31 45 35 58 56HPV type

%

North America

(n=1,311)

0

20

40

60

16 18 31 33 45 52 35 58HPV type

%

South and Central

America (n=1,427)

0

20

40

60

16 18 31 45 33 58 52 35HPV type

%

8 most common HPV types in 14,097 cases of

invasive cervical cancer by region70%

72%

67% 74%

76% 65%

IARC-ICE 2005

Preventive vaccines against HPV

• Which vaccines?

IARC-ICE 2005

HPV

16

IARC-ICE 2005

VLP

IARC-FIS

2002

IARC-ICE 2005

Location of main stages in HPV life cycle

IARC-ICE 2005

Product profile of prophylactic HPV vaccine

• Cervarix, GSK

• 16/18 High Risk HPV types

• Pure Cervical Cancer Vaccine

• Women only (10-55 yrs)

• 3 i.m. injections, 20 microg VLP

• Innovative AS04 adjuvant (MPL+Aluminium)

• Gardasil, Merck

• 16/18 high risk plus 6/11

low risk HPV types.

• Cervical cancer&genital

warts

• Women and Men (9-45

yrs).

• 3 i.m. injections, 40 microg

for HPV 11/16

• Conventional aluminium

IARC-ICE 2005

Conditions associated with

HPV types 16, 18, 6, 11

Clifford, BJ Ca 2003; Munoz Int J Cancer 2004; Brown J Clin Micro 1993; Carter Cancer Res

2001; Clifford Cancer Epi Biomarkers Prev 2005; Gissman Proc Natl Acad Science 1983;

Kreimer Cancer Epidemiol Biomarkers Prev 2005

HPV 16, 18 Estimated attributable %

– Cervical cancer 70 %

– High grade cervical abnormalities 50 %

– Low grade cervical abnormalities 30 %

– Anal cancer ~70 %

– Vulva / Vagina / Penile ~40 %

– Head and neck cancers ~3-12 %

HPV 6, 11

– Low grade cervical abnormalities 10 %

– Genital warts 90 %

– Recurrent respiratory papillomatosis (RRP) 90 %

IARC-ICE 2005

Preventive vaccines against HPV

• Which vaccines?

• Do they protect against cervical cancer?

IARC-ICE 2005

Combined PhaseII/III Efficacy studies of HPV6/11/16/18

vaccine

Mean follow up (since day 30 after 1st dose): 25 months

By protocol

EndpointVaccine †

(N=9,342)Placebo †

(N=9,400) Efficacy

95% Confidence

Interval

HPV 16/18-related CIN 2/3 or + 1 81 99% 93%,100%

HPV 16-related CIN 2/3 or + 1 68 99% 92%,100%

HPV 18-related CIN 2/3 or + 0 18 100% 77%,100%

HPV 16/18-related CIN 2 1 55 98% 89%,100%

HPV 16/18-related CIN3/AIS * 0 52 100% 93%,100%

† Women are counted once per line. A woman can in more than 1 line.

*CIN 3/AIS = Cervical Cancer Stage 0 FIGO

IARC-ICE 2005

Safety conclusions

From Eliav Barr

GARDASIL® is generally well tolerated in 9- to 26-year-old subjects

GARDASIL® is associated with:

an increase in injection-site AE, compared with placebo

higher incidence of low-grade fevers, compared with placebo

Individuals 9 to 26 years of age who receive GARDASIL® rarely

discontinue vaccination due to an AE

GARDASIL® is generally well tolerated in 9- to 26-year-old subjects

who are positive to >1 vaccine HPV type

Overall pregnancy outcomes (950 women) are comparable between

subjects who receive GARDASIL® or placebo

Further pharmacovigilance monitoring is planned

IARC-ICE 2005

Preventive vaccines against HPV

• Which vaccines?

• Do they protect against cervical cancer?

• Duration of efficacy in women without

evidence of current or previous infection with

vaccine HPV types?

IARC-ICE 2005

Vaccine efficacy for persistent infection

up to 4.5 years (intention-to-treat)

Harper et al, 2006

Placebo Vaccine

women Event women Efficacy

rate % (95%CI)

HPV 16 470 2.3 481 93.4

(74.0-99.2)

HPV 18 470 0.6 481 100.0

(42.8-100.0)

HPV 16/18 470 2.7 481 94.4

(78.2-99.4)

IARC-ICE 2005

Vaccine efficacy for incident infection

up to 4.5 years (intention-to-treat)

Harper et al, 2006

Placebo Vaccine

women Event women Efficacy

rate % (95%CI)

HPV 31 516 2.1 528 54.5

(11.5-77.7)

HPV 45 518 1.2 528 94.2

(63.3-99.9)

IARC-ICE 2005

Preventive vaccines against HPV

• Which vaccines?

• Do they protect against cervical cancer?

• Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types.

• Efficacy in women with evidence of current or previous infection with vaccine HPV types?

IARC-ICE 2005

Efficacy of HPV6-11-16-18 vaccine from 4 trials

against HPV16/18-related CIN2+

CIN2+ / Women

Vaccine Placebo Efficacy

By protocol 0 / 8487 53 / 8460 100%

(93%-100%)

By intention to treat 122 / 9831 201 / 9896 39%

(23%-52%)

Among women already

exposed to HPV16/18 122 / 1344 148 / 1436 12%

(non-significant)

IARC-ICE-2006

IARC-ICE 2005

Preventive vaccines against HPV

• Which vaccines?

• Do they protect against cervical cancer?

• Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types.

• Efficacy in women with evidence of current or previous infection with vaccine HPV types.

• Will screening benefit from preventive HPV vaccines?

IARC-ICE 2005

EUROPE

Cancer

73%

HSIL

57%

LSIL

24%

ASCUS 19%

Clifford et al, in press

Fraction of cervical lesions prevented by HPV 16/18 vaccine in

Europe and approximate number prevented per year in Italy

(assuming no protection against other types)

ITALY

Cancer : 2,500

HSIL : 8,400

LSIL : 11,300

ASCUS : 17,500

IARC-ICE 2005

Vaccines against HPV

• Which vaccines.

• Consequences on diseases.

• Consequence on the behaviour of the

women or the virus.

IARC-ICE 2005

Main reason for not having sex among

adolescents who have never had sex: NSFG 2002

25

20

10

58

38

1917

7 7

12

31

0

5

10

15

20

25

30

35

40

45

%

Males

Females

Abma et al, 2004; Vital and Health Statistics, Series 23, No 24.

From Nicole Liddon

Against

religion/

morals

Don’t want

to get (a

female)

pregnant

Haven’t

found

right

person

Don’t

want

STD

In a

relationship,

waiting for

right time

Other

IARC-ICE 2005

Impact of vaccine on sexual behaviour

From Nicole Liddon

Adolescent sexual behaviour indicates an opportunity

during early adolescence for HPV vaccine delivery

Unlikely sexual behavioural disinhibition will result from

HPV vaccine:

• Multiple other factors associated with adolescent sexual risk

• Fear of STD not apparent major motivation for abstinence

• No evidence of behavioral disinhibition in other similar fields

IARC-ICE 2005

Changes in the virus

• HPV type replacement can occur only if there is: a) partial competition of different types during natural history and b) the vaccine does not protect against types naturally competed against.

• In reality, a) anti-HPV ab+ women have strong risk to be also positive for ab against other types, and b) large studies of multiple-type infections did not find types that do not go together.

• Cross-protection stronger with vaccine than natural infection.

• Viral escape mutants can occur if a virus has high mutation rate (HIV, HCV).

• However, HPV mutation rate is very low (approx 2% since human origin) and HPV 16 strains and variants all over the world are a single serotype.

IARC-ICE 2005

Preventive vaccines against HPV

• Which vaccines?

• Do they protect against cervical cancer?

• Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types.

• Efficacy in women with evidence of current or previous infection with vaccine HPV types.

• Will screening benefit from preventive HPV vaccines?

• Any consequence on the behaviour of the women or the virus?

• What next?

IARC-ICE 2005

June, 2006: US Food and Drug Administration

approves HPV 6/11/16/18 Vaccine. The 3-shot , $ 360

series available by July 2006 in the US and few

other countries.

September, 2006: the European Medicines Agency approves the same vaccine.

• Quadrivalent vaccine already licensed in 50 countries.

• Efficacy trials in older women and males still on-going.

IARC-ICE 2005

Challenges to introduction, especially in

developing countries

1. Accurate and accessible information on HPV generally not available

2. Socio-cultural barriers to HPV vaccine unclear

3. Health delivery strategies/systems for reaching adolescent girls limited

4. Vaccine affordability and financing not yet known

5. Demand for/uptake of vaccine not yet known, so supply is hard to predict

6. Interaction with screening programs not yet clear

7. Competition with other new vaccines and health needs

Longer-term efficiency trials are still necessary